In order to prepare solid, shaped dosage forms from fine particles or powders comprising therapeutic agents, it has generally been necessary to process the powders in a manner to improve their flowability, cohesiveness and other characteristics which will enable the resulting material to be fabricated by conventional processes such as tableting, encapsulation, molding, etc. into a satisfactory unit form that can suitably deliver an agent into the environment of use.
Various processes have therefore been developed for modifying starting powders or other particulate materials, in which typically the powders are gathered together with a binder material into larger permanent free-flowing agglomerates or granules referred to collectively as a "granulation." For example, solvent-assisted "wet" granulation processes are generally characterized in that the powders are combined with a binder material and moistened with water or an organic solvent under conditions to result in formation of a wet granulated mass from which the solvent must then be evaporated. Such processes, while widely employed, have certain recognized limitations arising from the use when necessary of non-aqueous solvents which may be environmentally deleterious, and furthermore may not be readily adaptable in connection with moisture or heat sensitive medicaments. Alternatively, the known "dry granulation" processes, which can depend on fairly complicated milling schemes to produce a suitable granulation, also have acknowledged disadvantages.
A "direct compression" process has in limited cases provided a simpler and more economical means of preparing compressed dosage forms.
In such a process, the therapeutically active ingredient is combined with a binder-diluent or vehicle which itself is characterized in having the requisite properties for tableting, such as flowability, appropriate particle size distribution, binding ability, acceptable bulk and tap density and dissolution properties, and the resulting blend can therefore be "directly" provided to a die cavity or mold for compaction, without prior granulation. See Shangraw, "Compressed Tablets by Direct Compression," in Pharmaceutical Dosage Forms, 2d Ed., 1989, Vol. 1, pp. 195-246. The resulting compressed dosage form often provides improved stability and dissociation profiles, as well as batch-to-batch uniformity, relative to "wet" or "dry" granulated dosage forms.
A suitable direct compression vehicle for a given application is preferably also tailored, for example, to be compatible with the active ingredient, to resist physical or chemical change on aging, to be air, moisture and heat-stable, have sufficient capacity for the active ingredient in the dosage form, accept colorants uniformly when necessary, and not interfere with biological availability.
Materials employed by the art which to varying degrees fulfill the requirements of a direct compression vehicle include water soluble materials such as various forms of lactose (e.g., spray-dried lactose, Fast Flow.RTM. lactose, anhydrous lactose), as well as sucrose, dextrose, sorbitol, mannitol and maltodextrin, and relatively insoluble materials such as microcrystalline cellulose (e.g., Avicel.RTM.), starch, dicalcium phosphate dihydrate, and calcium carbonate.
However, such materials, while often comprising a relatively large proportion by weight of the tableted formulation in order to impart full advantage of their compression properties, nevertheless in themselves are generally insufficient to regulate the rate of disintegration of the dosage form or release of the medicament, and therefore must often be accompanied by various additional excipients having such a rate-control effect, the latter which (given practical limitations on the size of the dosage form) may be confined to low concentrations at which the rate control effect is not completely satisfactory.
It has therefore been an object to identify a directly compressible vehicle which can exert a rate control function in the prepared dosage form.
In particular, it has been an object to prepare both immediate and sustained release therapeutically active dosage forms comprising such an excipient.